Prognostic Relevance of Erythropoiesis-Stimulating Agent Dose Requirements in PIVOTAL and its Implications for the Potential Mechanisms of Intravenous Iron Benefit in Maintenance Hemodialysis Patients

Background Decreased erythropoiesis-stimulating agent (ESA) requirements might explain the benefits of high-dose intravenous (IV) iron in PIVOTAL. However, as iron can be beneficial via non-erythropoietic pathways, higher iron doses might relate to better outcomes independently of ESA doses. This post-hoc analysis examines whether reduced ESA exposure mediated the benefits of IV iron, and whether IV iron exerted additional effects independent of erythropoiesis in PIVOTAL. Methods We analysed data from 2141 participants in the PIVOTAL trial. Primary endpoint was all-cause mortality (ACM) or nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Results Baseline median IQR ESA dose was 8000 5000, 10000 IU/week and similar in both treatment arms. Over 24 10, 33 months, 658 (31%) patients met the primary endpoint, and ACM occurred in 515 (24%) patients. In adjusted Cox models, higher baseline ESA doses (per 10,000 IU/week) were associated with increased risks (primary endpoint: HR 1.31 95% CI: 1.16, 1.49, P < 0.001; ACM: HR 1.33 95% CI: 1.15, 1.53, P < 0.001) in reactive patients. Over time, proactive patients had lower ESA (25,98017320, 43300 vs. 34,64025980, 56290 IU/month) and higher iron (250193, 300 vs. 127 88, 171 mg/month) doses. In adjusted Cox models with time-varying covariates, higher ESA doses (≥ 34640 IU/month) were associated with increased risks (primary endpoint: HR 1.5895% CI:1.34,1.86, P<0.001; ACM: HR 1.8395% CI:1.51,2.20, P<0.001), while higher iron doses (≥200 mg/month) were linked to reduced risks (primary endpoint: HR 0.7895% CI:0.67, 0.92, P=0.002; ACM: HR 0.780.65, 0.93, P=0.001) in the total population. Conclusion Lower ESA requirements predicted better outcomes in PIVOTAL, but higher IV iron doses remained protective even after accounting for ESA doses. These findings provide the first evidence within PIVOTAL that IV iron may exert protective effects independent of ESA dose requirements and hemoglobin levels, supporting a role for non erythropoietic mechanisms.